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AGENCY:

National Institutes of Health, Public Health Service, DHHS.

ACTION:

Notice.

SUMMARY:

The inventions listed below are owned by agencies of the U.S. Government and are available for licensing in the U.S. in accordance with 35 U.S.C. 207 to achieve expeditious commercialization of results of federally-funded research and development. Foreign patent applications are filed on selected inventions to extend market coverage for companies and may also be available for licensing.

ADDRESSES:

Licensing information and copies of the U.S. patent applications listed below may be obtained by writing to the indicated licensing contact at the Office of Technology Transfer, National Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-3804; telephone: 301/496-7057; fax: 301/402-0220. A signed Confidential Disclosure Agreement will be required to receive copies of the patent applications.

Four Chimpanzee Monoclonal Antibodies that Neutralize Hepatitis A Virus

This invention claims antibodies and/or fragments thereof specific for hepatitis A virus (HAV) and the use of the antibodies in the diagnosis, prevention, and treatment of hepatitis A. Hepatitis A is the most common type of hepatitis reported in the United States, which reports an estimated 134,000 cases annually, and infects at least 1.4 million people worldwide each year. HAV is a positive sense RNA virus that is transmitted via the fecal-oral route, mainly through contaminated water supplies and food sources. HAV is thought to replicate in the oropharynx and epithelial lining of the intestines, where it initiates a transient viremia and subsequently infects the liver. Humoral immunity has been shown to provide an effective defense against Hepatitis A. Prior to the availability of the current inactivated virus vaccines, pooled human immune globulin preparations were routinely used to protect individuals traveling to areas of the world where HAV is endemic. Chimpanzees are susceptible to infection with HAV and can produce antibodies that neutralize the virus. Chimpanzee immunoglobulins are virtually identical to those of humans; thus, they have the same potential as human antibodies for clinical applications. The inventors have shown that the four chimpanzee monoclonal antibodies described in the patent application neutralized HAV strains HM-175, AGM-27, and the HM-175 VP3-070 mutant. Since only a single serotype of HAV has been identified, these antibodies are predicted to neutralize most, if not all, isolates of HAV.

Formyl peptides are short peptides generated by bacterial or mitochondrial endopepdidase cleavage of the first few amino acids including the N-formyl-modified methionine group of proteins. They bind to specific receptors on phagocytic cells and platelets, and induce directed migration or chemotaxis. Human phagocytes express two N-formyl peptide receptors, FPR (N-formyl peptide receptor) and FPRL-1 (FPR-like 1), both of which couple to pertussis toxin-sensitive G proteins. FPR binds N-formyl peptides at a 1000 fold higher affinity than FPRL 1 and is attributed with inducing chemotaxis. Based on their chemotactic actions, it has been hypothesized that N-formyl peptides attract phagocytes and platelets to sites of infection and injury and therefore play an important role in microbicidal and other host defense activities. In particular, platelets carry CD154 or CD40 ligand on their surface and can provide induction of dendritic cell maturation and co-stimulatory molecule expression, thus regulating immune versus tolerance responses.

Claimed in the invention are compositions of N-formyl peptides and derivatives of N-formal peptides, use of N-formyl peptides to stimulate an immune or inflammatory response, and methods of using N-formal peptide receptor inhibitors, such as blocking antibodies or other receptor antagonists, for inhibiting inflammation. Also claimed in the invention are methods of mobilizing platelets at an injury site and methods of wound healing at an injury site comprising administering N-formal peptides to the site.

Vaccination Strategies To Provide Protection Against the Ebola Virus

This invention describes a method for vaccination against Ebola virus. Outbreaks of hemorrhagic fever caused by the Ebola virus, particularly the Zaire subtype, are associated with high mortality rates. The virus is very contagious, and during an outbreak, presents a threat to anybody who comes into contact with an infected person. Because the virus progresses so rapidly and the mortality rate is so high, there is little opportunity to develop natural immunity, making vaccination a promising intervention. This invention relates to a vaccine strategy employing DNA and adenoviral vectors expressing proteins associated with the Ebola virus. This vaccine strategy, a DNA prime with an adenoviral boost, elicits a protective immune response in primates. A vaccine was designed to optimize expression by incorporating genes for two subtypes of the glycoprotein (Zaire and Sudan) and minimizes toxicity by eliminating the trans-membrane region. The specific genes identified may be used for gene-based or protein-based vaccines that will prevent Ebola infection.

This application claims use of CpG oligodeoxynucleotides (ODN) to generate mature dendritic cells (DC). Also claimed in the application are synergistic use of CpG ODNs with cytokines, chemokines, or other factors to induce the maturation of monocytes to dendritic cells. Dendritic cells play a critical role in the generation of adaptive immune responses. Dendritic cells excel at presenting antigen to naive T lymphocytes. Large numbers of highly active DC are necessary for prevention and/or treatment of cancer and infectious diseases. Current processes for generating mature DC from peripheral blood mononuclear cells (PBMC) involve incubating PBMC with GM-CSF plus IL-4 for one week followed by monocyte-conditioned medium for two to seven days. These processes are inefficient, expensive and do not uniformly generate DC with full functional activity. The current invention is based on the observation that bacterial DNA and synthetic ODNs containing unmethylated “CpG motifs” promote the maturation of murine antigen presenting cells (APC) in vitro. The invention is further described in Ishii KJ et al., “Genomic DNA released by dying cells induces the maturation of APCs,” J. Immunol. 2001 Sep 1;167(5):2602-7.

Use of Sterically Stabilized Cationic Liposomes To Efficiently Deliver CpG Oligonucleotides in vivo

Immunostimulatory CpG oligonucleotides (ODN) show promise as immune adjuvants, anti-allergens, and immunoprotective agents. Increasing the bioavailability and duration of action of CpG ODN should improve their therapeutic utility. This invention claims use of Sterically Stabilized Cationic Liposomes (SSCL) to deliver CpG ODNs. In addition to use of SSCL to deliver CpG ODNs, SSCL-CpG compositions are also claimed in the patent application. The claimed SSCL comprise three distinct phospholipid elements, DC-CHOL (which increases liposome membrane stability while improving the uptake and encapsulation of DNA), DOPE (a pH-sensitive neutral lipid that improves the cytosolic delivery of CpG ODNs following internalization), and PEG-PE (which stabilizes the liposome and also facilitates cellular uptake). The inventors have conducted both in vivo and in vitro studies using the SSCL-CpG compositions, showing that in vitro, liposome-encapsulated CpG ODNs stimulated significantly more interferon-gamma (IFN-γ) production than free CpG ODNs. The in vivo testing the inventors completed show that SSCL encapsulation of CpG ODNs increase the magnitude and duration of the activity of the CpG ODNs in vivo; when CpG-SSCLs were administered to mice infected with L. monocytogenes (listeria), one hundred percent of the infected mice survived four weeks post-treatment. The invention is further described in Gursel I et al., “Sterically stabilized cationic liposomes improve the uptake and immunostimulatory activity of cpg oligonucleotides,” J. Immunol. 2001 Sep 15; 167(6):3324-8.

Identification of DNA Sequence Motifs That Suppress the Immune Response to CpG DNA

This invention claims compositions and methods for suppressing CpG oligonucleotide immunostimulatory action with suppressive motifs comprising mammalian DNA. The sequences of the suppressive motifs claimed in the application comprise multimeric repeats, which have a tendency to form “G-tetrads,” which suppress CpG induced immune activation. The inventors have found through in vivo and in vitro experimentation that these suppressive motifs inhibited CpG DNA induced proliferation and cytokine production. Further experimentation by the inventors has shown that ODNs containing the most said repeats were the most suppressive. There are multiple therapeutic uses for the suppressive oligodeoxynucleotides (ODNs) of the invention, such as use in the prevention or treatment of septic shock, adult respiratory distress syndrome (ARDS), or autoimmune disease. Furthermore, the inventors disclose that eliminating suppressive motifs from the plasmid backbone of DNA vaccines may improve vaccine immunogenicity by maximizing the effect of CpG motifs present in such vectors. The advantages associated with use of suppressive motifs is that therapeutics based on this technology would avoid many of the unwanted side effects associated with current immunosuppressive therapeutics.